Myocardial ischemia, and its relief by coronary artery reperfusion, are among the most important health problems currently in the U.S. In the renewal application there are five major hypotheses to be tested. (1) EDRF (NO) sensitivity is enhanced in stunned coronary arteries. The upregulation of NO is part of the autoregulatory mechanism to ischemia, and potentially part of the mechanism of maintenance of blood flow with subacute and chronic coronary stenosis. (2) Myocardial stunning and myocardial hibernation have similar mechanisms. (3) Responses to sympathomimetic amines are augmented in the presence of a chronic coronary artery stenosis. (4) Decreasing the heterogeneity of blood flow is a major protective mechanism underlying pre-conditioning. These studies are designed to provide insight into basic mechanisms of myocardial ischemia and its relief by coronary artery reperfusion. One unique feature of the current research proposal is to examine the effects of coronary artery occlusion and reperfusion, as well as chronic coronary constriction induced with stenoses and ameroid devices, along with regional blood flow (radioactive microspheres. A second important feature is to measure regional myocardial function, i.e., endocardial and epicardial wall thickening and segment shortening. A third feature is to correlate these measurements with regional biochemistry and molecular biology. A new aspect of the renewal includes collaborative studies on intermediary energy metabolism using NMR spectroscopy. There are 3 major aims related to this collaborative effort: (1) To determine the activity of oxidative from nonoxidative substrate utilization and distinguish the contributions of anaerobic glycolysis from glucose oxidation to ATP synthesis during adaptation to chronic coronary artery stenosis, i.e., potentially hibernating myocardium. (2) To perform 13C NMR spectroscopy to assess its potential for detecting differences in intermediary metabolism during myocardial pre-conditioning and susceptibility to ischemic cell death. (3) To utilize in vivo 13P NMR spectroscopy and chemical assays of biopsy specimens to determine the energic basis for observed differences in susceptibility to myocardial infarction. Using this approach, the mechanisms underlying the unique properties of the myocardium may be identified.